CN104529775B - α asarum alcohol esters and preparation method and application - Google Patents

α asarum alcohol esters and preparation method and application Download PDF

Info

Publication number
CN104529775B
CN104529775B CN201410699506.6A CN201410699506A CN104529775B CN 104529775 B CN104529775 B CN 104529775B CN 201410699506 A CN201410699506 A CN 201410699506A CN 104529775 B CN104529775 B CN 104529775B
Authority
CN
China
Prior art keywords
compound
formula
alcohol ester
preparation
asarum alcohol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410699506.6A
Other languages
Chinese (zh)
Other versions
CN104529775A (en
Inventor
郑晓晖
秦方刚
白亚军
王世祥
张毅
何希瑞
刘佩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
XI'AN PUYANG SCIENCE AND TECHNOLOGY DEVELOPMENT Co Ltd
Northwest University
Original Assignee
XI'AN PUYANG SCIENCE AND TECHNOLOGY DEVELOPMENT Co Ltd
Northwest University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by XI'AN PUYANG SCIENCE AND TECHNOLOGY DEVELOPMENT Co Ltd, Northwest University filed Critical XI'AN PUYANG SCIENCE AND TECHNOLOGY DEVELOPMENT Co Ltd
Priority to CN201410699506.6A priority Critical patent/CN104529775B/en
Publication of CN104529775A publication Critical patent/CN104529775A/en
Priority to PCT/CN2015/095686 priority patent/WO2016082780A1/en
Priority to PL15863145T priority patent/PL3225616T3/en
Priority to US15/529,283 priority patent/US10131619B2/en
Priority to RU2017121591A priority patent/RU2673887C1/en
Priority to JP2017527866A priority patent/JP6506841B2/en
Priority to SI201531204T priority patent/SI3225616T1/en
Priority to KR1020177017335A priority patent/KR102029898B1/en
Priority to SG11201704239PA priority patent/SG11201704239PA/en
Priority to DK15863145.7T priority patent/DK3225616T3/en
Priority to MYPI2017701893A priority patent/MY175619A/en
Priority to EP15863145.7A priority patent/EP3225616B1/en
Priority to AU2015353112A priority patent/AU2015353112B2/en
Priority to CA2968652A priority patent/CA2968652C/en
Priority to NZ732395A priority patent/NZ732395A/en
Priority to HUE15863145A priority patent/HUE049249T2/en
Priority to IL252461A priority patent/IL252461B/en
Application granted granted Critical
Publication of CN104529775B publication Critical patent/CN104529775B/en
Priority to HK18103381.1A priority patent/HK1243995A1/en
Priority to CY20201100376T priority patent/CY1123193T1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/33—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with hydroxy compounds having more than three hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/614—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety of phenylacetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Emergency Medicine (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

The present invention relates to α asarum alcohol esters and preparation method and application.The chemical structure of general formula of involved α asarum alcohol esters is shown in formula I.Involved application be above-claimed cpd be used to preparing it is calm, calm the nerves, anti-senile dementia, anticonvulsion, anti-epileptic, the application of antidepressant.

Description

α-asarum alcohol ester and preparation method and application
Technical field
The invention mainly relates to the preparation method of α-asarum alcohol ester and its for it is calm, calm the nerves, it is anti-senile dementia, anti-frightened Faint, anti-epileptic, antidepressant drug research.
Background technology
Grass-leaved sweetflag, first record in《Sheng Nong's herbal classic》, it is top grade, from Araeceae herbaceos perennial stone Chang Pu Acorus tatarinowii Schott. dry rhizome.It is warm-natured, pungent, hardship.Enter the heart, stomach, the gas with fragrance is pungent The scattered power of warm row, can with removing dampness to restore normal functioning of the stomach, again can dissipating phlegm for resuscitation, the effects such as with intelligence development inducing resuscitation, be usually used in treatment apoplexy, coma due to blocking of the respiratory system insane Epilepsy, coma, forgetful etc..Main chemical compositions are volatile oil, amino acid and carbohydrate etc., and volatile oil mainly contains beta-Asarone, α- Asarone etc..Modern pharmacological research thinks that grass-leaved sweetflag has the effect such as anti-dementia, neurocyte protection, anti-mutation, anti-epileptic.
Polygala, is embodied in first《Sheng Nong's herbal classic》, it is top grade, from milk wort polygala Polygala Tenuifalia Willd. or ovum leaf polygala Polygala sibirica L. dry root.It is polygala bitter, pungent, it is warm-natured.Have The effect of intelligence promoting and tranquilization, dissolving phlegm drive swollen.In polygala chemical composition mainly comprising triterpene saponin, sugar esters,Ketone, also contains A small amount of alkaloid, cumarin, lignin etc..Research shows, polygala anti-dementia, brain protection, calm, anticonvulsion, antidepression, There is excellent activity in terms of eliminating phlegm and relieving cough, protection cardiovascular and cerebrovascular.
Shasha WANG etc. is by the way that after to Oral Administration in Rats milkwort extract, the bar ratio of mouse penta can be extended by being found that in blood and bile The active material 3,4,5- trimethoxy cinnamic acids (TMCA) of the appropriate sodium length of one's sleep, methyl 3,4,5- trimethoxy cinnamic acids (M- TMCA) and p-methoxycinnamic acid (PMCA), the natural precursor medicine containing TMCA in polygala water extract is pointed out.[Wang S.S.Wakan Iyakugaku Zasshi,1995,12(2),102]
The grade that icepro is faced upward carries out structure split to TMCA, has obtained 3,4,5- trimethoxy cinnamide compounds, finds It has good anti-convulsant activity.[icepro faces upward it, medical industry, 1987,18 (2):56]
Based on α-asarone in TMCA in polygala and grass-leaved sweetflag it is calm, calm the nerves, in terms of anticonvulsion, neurocyte protection With good pharmacological activity, we devise 3,4,5- trimethoxy cinnamic acid α-kakuol by structure and pharmacophore split Ester and a series of ester derivatives by core of α-kakuol, to anti-senile dementia, brain protection, it is calm, anticonvulsion, anti- Screening obtains the chemical new drug of more curative effect in terms of depression.
The content of the invention
The invention provides α-asarum alcohol ester, its general structure is shown in formula I：
Wherein：
R is side chain or straight chain C1-12Alkyl, alkenyl or alkynyl；C3-9Cycloalkyl, substituted cycloalkyl；C3-9Cycloalkenyl group, Substituted cycloalkenyl；Aryl, monosubstituted aryl or polysubstituted aryl；Heterocyclic aryl, monosubstituted heterocyclic aryl or polysubstituted heterocycle virtue Base；Amino acidic group.
Further alternative, described R is arylmethyl, monosubstituted arylmethyl or polysubstituted arylmethyl；It is fragrant ethyl, monosubstituted Or polysubstituted fragrant ethyl；Aromatic ethylene base, monosubstituted or polysubstituted aromatic ethylene base；Substituted benzene oxygen ethyl.
Further optional, described R is：
Present invention also offers the preparation method of above-mentioned α-asarum alcohol ester, method includes：By Compounds of formula II and formula III, catalyst in molar ratio 1.0~2.0:1.0~2.0:0.1~1.0 sequentially adds containing appropriate organic solvent reaction vessel In, until completely dissolved, add dehydrating agent, the mol ratio of dehydrating agent and Compounds of formula II is 1~2:1,5- is stirred at room temperature 20 hours, stop reaction, ethyl acetate/water separation, organic phase anhydrous sodium sulfate drying, concentration, column chromatography separating purification；
The catalyst is pyridine, 2,4,6- trimethylpyridines, 2,6- lutidines, 2,6- di-t-butyl -4- methyl Pyridine and one kind in DMAP (DMAP) are wherein combined；
The organic solvent is dichloromethane, chloroform, tetrachloromethane, tetrahydrofuran, ethyl acetate, methyl tertbutyl Ether, ether, 1,4- dioxane, N,N-dimethylformamide, 1-METHYLPYRROLIDONE, DMAC N,N' dimethyl acetamide and dimethyl It is a kind of or be wherein combined in sulfoxide；
The dehydrating agent is dicyclohexylcarbodiimide (DCC), 1- (3- dimethylaminopropyls) -3- ethyl carbodiimides Hydrochloride (EDCI) or DIC (DIC).
The present invention also provide simultaneously can above-mentioned α-asarum alcohol ester another preparation method, method includes：
α-kakuol generates α-asarum alcohol ester with compound of formula III under Mitsunobu reaction conditions：
Further, method includes：By α-kakuol, compound of formula III, azo-compound, organic phosphorus compound massage You are than being 1~1.5:1~1.5:1~1.5:1~1.5 is dissolved in dry tetrahydrofuran, reacts at room temperature 10-48 hours, acetic acid Ethyl ester/water separation, organic phase anhydrous sodium sulfate drying, concentration, column chromatography separating purification.
Optionally, the azo-compound is diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), azodicarbonyldipiperidine (ADDP), N, N, N ', N '-tetramethyl azodicarboxy acid amides (TMAD), N, N, N ', N '-four Isopropyl azodicarboxy acid amides (TIPA) or the azepine Xin Yin -3,8- of 4,7- dimethyl -3,4,5,6,7,8- hexahydros -1,2,4,7- four Diketone (DHTD).
Optionally, organic phosphorus compound is triphenylphosphine, tributylphosphine or trimethyl phosphorus.
Invention further provides the alloisomerism of above-claimed cpd or the mixture of its different Stereoisomeric compounds.
Present invention simultaneously provides can above-claimed cpd be used to preparing it is calm, calm the nerves, anti-senile dementia, anticonvulsion, anti-epileptic, The application of antidepressant.
Embodiment
The invention provides a class α-asarum alcohol ester, its structural formula is as shown in formula I：
Wherein, in formula I, R is side chain or straight chain C1-12Alkyl, alkenyl or alkynyl；C3-9Cycloalkyl, substituted cycloalkyl Or cycloalkenyl group, substituted cycloalkenyl；Aryl, monosubstituted or polysubstituted aryl；Heterocyclic aryl, monosubstituted heterocyclic aryl or polysubstituted miscellaneous Cyclophane base；Arylmethyl, monosubstituted arylmethyl or polysubstituted arylmethyl；Fragrant ethyl, monosubstituted or polysubstituted fragrant ethyl；Aromatic ethylene Base, monosubstituted or polysubstituted aromatic ethylene base；Substituted benzene oxygen ethyl；Amino acidic group.
The preparation method of compound of the present invention is：
Optionally, method (1)：Compounds of formula II is obtained with compound of formula III in the presence of dehydrating agent/catalyst Corresponding α-asarum alcohol ester (compound of Formula I)；
Wherein, by Compounds of formula II and general formula III, catalyst in molar ratio 1.0~2.0:1.0~2.0:0.1~1.0 Sequentially add containing in appropriate organic solvent reaction vessel, until completely dissolved, add dehydrating agent (dehydrating agent and formula IIization The mol ratio of compound is 1~2:1), it is stirred at room temperature 5-20 hours, stops reaction, the separation of ethyl acetate/water, organic phase is with anhydrous Sodium sulphate is dried, concentration, column chromatography separating purification.Wherein, preferred formula II compounds are with general formula III, catalyst molar ratio 1.0:1.0~1.2:0.1~0.3.
Used catalyst is included：Pyridine, 2,4,6- trimethylpyridines, 2,6- lutidines, 2,6- di-t-butyl -4- first Yl pyridines, DMAP are wherein combined, and preferably DMAP is used as catalyst；
Organic solvent used is included：Dichloromethane, chloroform, tetrachloromethane, tetrahydrofuran, ethyl acetate, methyl- tert Butyl ether, ether, 1,4- dioxane, N,N-dimethylformamide, 1-METHYLPYRROLIDONE, DMAC N,N' dimethyl acetamide, two Methyl sulfoxide is wherein combined, and preferably DMF, dichloromethane, tetrahydrofuran are used as solvent；
Dehydrating agent used is：Dicyclohexylcarbodiimide (DCC), 1- (3- dimethylaminopropyls) -3- ethyls carbon two are sub- Amine hydrochlorate (EDCI), DIC (DIC), preferably EDCI is used as dehydrating agent；
Optionally, method (2), compound of formula III first generates chloride compounds and reacted again with Compounds of formula II, obtains Corresponding α-asarum alcohol ester (compound of Formula I), it is specific as follows：Under condition of ice bath, chlorination is added into compound of formula III Sulfoxide, flows back 2-5 hours, cooling, the excessive thionyl chloride of vacuum distillation, and adding tetrahydrofuran in residue is sufficiently stirred for, and obtains To the acyl chlorides tetrahydrofuran solution of compound of formula III, under condition of ice bath, by the acyl chlorides tetrahydrochysene of above-mentioned compound of formula III Tetrahydrofuran solution is added to containing in the solution with Compounds of formula II and the tetrahydrofuran of pyridine, is stirred 10-20 minutes, then heat up Backflow 3-4 hour, after reaction completely, cools down, is filtered to remove pyridine hydrochloride, and filtrate decompression is evaporated off tetrahydrofuran, and ethyl acetate/ Water is separated, organic phase anhydrous sodium sulfate drying, concentration, column chromatography separating purification.
Wherein, compound of formula III and the mol ratio of thionyl chloride are 1:10 to 1:100, preferred formula III compounds with The mol ratio of thionyl chloride is 1:50.
Optionally, method (3), Compounds of formula II generates logical with compound of formula III under Mitsunobu reaction conditions Formula compound I.Concrete mode is：
It is 1~1.5 in molar ratio by Compounds of formula II, compound of formula III, azo-compound, organic phosphorus compound: 1~1.5:1~1.5:1~1.5 is dissolved in dry tetrahydrofuran, reacts at room temperature 10-48 hours, ethyl acetate/water separation, has Machine mutually uses anhydrous sodium sulfate drying, concentration, column chromatography separating purification, preferred formula II compounds, compound of formula III, azo Compound, organic phosphorus compound mol ratio are 1:1~1.1:1~1.2:1~1.2.
Wherein, azo-compound includes diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), idol The piperidines (ADDP) of two formyl of nitrogen two, N, N, N ', N '-tetramethyl azodicarboxy acid amides (TMAD), N, N, N ', N '-tetra isopropyl is even Nitrogen dicarboxamide (TIPA), the azepine Xin Yin -3,8- diketone of 4,7- dimethyl -3,4,5,6,7,8- hexahydros -1,2,4,7- four (DHTD), preferably DIAD, DEAD.
Organic phosphorus compound includes triphenylphosphine, tributylphosphine, trimethyl phosphorus, triphenylphosphine.
There may be one or more asymmetric carbon atoms in compound of Formula I of the present invention, its any alloisomerism or its Stereomeric any mixture is the part of the present invention.
Compound of Formula I of the present invention be used for it is calm, calm the nerves, anti-senile dementia, anticonvulsion, anti-epileptic, antidepressant medicine Research.
Involved α-kakuol preparation method includes in the present invention：
(1) compound IV and compound V obtains compound VI in the presence of fatty alcohol through catalyst reaction：
Wherein R1Selected from C1-C5Straight or branched alkyl；
(2) reducing compound VI obtains compound II：
Step (1) is that compound V and fatty alcohol is first back flow reaction 3-12 hours in dimethylbenzene, toluene or benzene, enters one Optional 4-10 hour is walked, is cooled to after room temperature, 2,4,5- TMBs (compound IV) and catalyst is added, then return Stream reaction 5-24 hours, it is further optional 8-14 hours, obtain compound VI；Fatty alcohol used in step (1) is methanol, One kind in ethanol, propyl alcohol, isopropanol, butanol, isobutanol, n-amyl alcohol and isoamyl alcohol is wherein combined, further optional Methanol and ethanol；In one kind or wherein any combination fatty alcohol and compound V molar ratio 1:1~1:10, further Optional fatty alcohol is 1 with compound V molar ratio:1~1:4；Catalyst used be pyridine, 2,4,6- trimethylpyridines, One kind in 2,6- lutidines, 2,6- di-t-butyl -4- picolines, DMAP, piperidines and nafoxidine Or be wherein combined；The molar ratio of catalyst and 2,4,5- TMBs is 0.1:1~2:1.
Reducing agent used by step (2) is that sodium borohydride, double (2- methoxyethoxies) sodium aluminates of dihydro, lithium aluminium hydride reduction or two are different Butyl aluminum hydride；Reducing agent and compound VI ratio are 1:1~10:1；Solvent for use be tetrahydrofuran, 1,4 dioxane, Dimethyl second diether, toluene, benzene, dimethylbenzene, ether, methyl tertiary butyl ether(MTBE), dichloromethane, dichloroethanes, chloroform, tetrachloro One kind in methane and n-hexane is wherein combined；Reaction temperature is at -78 DEG C~25 DEG C；Reaction time is small 0.5~24 When between.
The present invention will be better understood when by following description, these embodiments are only explanation, favourable embodiment party of the invention Case not limited to this.
α-kakuol used takes following methods to synthesize in following examples：
The preparation of 2,4,5- trimethoxy cinnamic acid methyl esters
3L there-necked flasks, band thermometer, condenser pipe, be separately added into Maxwell acid 195.5g (1.35mol), methanol (50mL), Toluene (750mL), is heated to reflux after 4 hours at 110 DEG C, is cooled to room temperature, adds 2,4,5- TMBs 196.2g (1.0mol), pyridine 134.5g (1.7mol), piperidinyl-1 4.5g (0.17mol), are heated to reflux 18 hours, are concentrated under reduced pressure Afterwards, ethyl acetate (200mL) is added, water (200mL), extract and separate 3 times merges organic phase, after being concentrated under reduced pressure, and adds ethanol (1000mL), is put into refrigerator cold-storage and stays overnight, after precipitation to be precipitated, suction filtration, and 500mL ice ethanol is washed 3 times, obtains faint yellow solid 166.3g, yield 66%.
3L there-necked flasks, band constant pressure funnel, add LiAlH428.5g (0.75mol) (is dissolved in 250mL tetrahydrofurans In), stir 20 minutes under ice bath, add AlCl342.6g (0.32mol) (is dissolved in 150mL tetrahydrofurans), stirs 30 points Zhong Hou, at 0 DEG C, is slowly added dropwise 2,4,5- trimethoxy cinnamic acid methyl esters 63.1g (0.25moL) and (is dissolved in 200mL tetrahydrofurans In), slow heating is stirred 1 hour at room temperature.Water (23g), 10% NaOH (23mL), water (69mL) are slowly added to, is treated After Precipitation, suction filtration after being concentrated under reduced pressure, adds ethyl acetate (50mL), water (100mL), extract and separate 3 times merges organic Phase, anhydrous sodium sulfate drying, suction filtration is concentrated under reduced pressure, gained crude product through the isolated light yellow solid 28.0g of silica gel chromatographic column, Yield 50%.
Embodiment 1：
3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester
250mL single-necked flasks, are separately added into α-kakuol 11.20g (50.0mmol), 3,4,5- trimethoxy cinnamic acids 17.85g (75.0mmol), DMAP 1.83g (15.0mmol), dichloromethane (120mL), after stirring 30 minutes at room temperature, are added EDCI 14.38g (75.0mmol), react 6 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, add saturated carbon Sour hydrogen sodium solution, adjusts pH=7-8, is extracted, washed 3 times with ethyl acetate/aqueous systems, merges organic phase, and anhydrous sodium sulfate is done Dry, suction filtration is concentrated under reduced pressure, and gained crude product is through the isolated yellow solid 17.76g of silica gel chromatographic column, yield 80%.
M/z=[M+Na] 467.1684
1H NMR (600MHz, cdcl3) δ 7.64 (d, J=15.9Hz, 1H), 7.00 (t, J=7.9Hz, 2H), 6.76 (s, 2H), 6.51 (s, 1H), 6.39 (d, J=15.9Hz, 1H), 6.26 (dt, J=13.8,6.7Hz, 1H), 4.87 (d, J= 6.7Hz,2H),3.90(s,3H),3.88(s,9H),3.87(s,3H),3.84(s,3H).
13C NMR(600MHz,cdcl3)δ166.78(s),153.41(s),151.70(s),149.95(s),144.87 (s),143.29(s),140.07(s),129.92(s),129.23(s),128.84(s),125.93(s),121.30(s), 117.34(s),116.86(s),110.01(s),105.18(s),97.46(s),65.97(s),60.97(s),56.58(s), 56.50(s),56.13(s),56.06(s).
Embodiment 2：
Nicotinic acid α-asarum alcohol ester
100mL single-necked flasks, are separately added into α-kakuol 1.12g (5.0mmol), nicotinic acid 0.92g (7.5mmol), DMAP 0.18g (1.5mmol), DMF (20mL), after stirring 35 minutes at room temperature, add EDCI 1.44g (7.5mmol), reacts 8 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, adds saturated sodium bicarbonate solution, PH=7-8 is adjusted, is extracted, washed 3 times with ethyl acetate/aqueous systems, merges organic phase, anhydrous sodium sulfate drying, suction filtration, decompression Concentration, gained crude product is through the isolated yellow solid 0.82g of silica gel chromatographic column, yield 50%.
Embodiment 3：
Isonicotinic acid α-asarum alcohol ester
100mL single-necked flasks, be separately added into α-kakuol 0.90g (4.0mmol), isonicotinic acid 0.74g (6.0mmol), DMAP 0.15g (1.2mmol), chloroform (20mL), after stirring 30 minutes at room temperature, add EDCI 1.15g (6.0mmol), reacts 6 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, adds saturated sodium bicarbonate solution, PH=7-8 is adjusted, is extracted, washed 3 times with ethyl acetate/aqueous systems, merges organic phase, anhydrous sodium sulfate drying, suction filtration, decompression Concentration, gained crude product is through the isolated yellow solid 0.59g of silica gel chromatographic column, yield 45%.
Embodiment 4：
3,4,5- trimethoxy phenyl acetic acids α-asarum alcohol ester
100mL single-necked flasks, are separately added into α-kakuol 1.34g (6.0mmol), 3,4,5- trimethoxy phenyl acetic acids 2.03g (9.0mmol), DMAP 0.22g (1.8mmol), DMF (30mL), after stirring 30 minutes at room temperature, EDCI 1.73g (9.0mmol) are added, are reacted 6 hours at room temperature, TLC monitoring reactions after raw material reaction terminates, add saturation Sodium bicarbonate solution, adjusts pH=7-8, is extracted, washed 3 times with ethyl acetate/aqueous systems, merges organic phase, anhydrous sodium sulfate Dry, suction filtration is concentrated under reduced pressure, and gained crude product is through the isolated yellow solid 1.68g of silica gel chromatographic column, yield 65%.
Embodiment 5：
L-PROLINE α-asarum alcohol ester
(i) 100mL there-necked flasks, band thermometer, are separately added into L-PROLINE 2.30g, (20.0mmol), Isosorbide-5-Nitrae-dioxy six Ring (10mL), 2mol/L sodium hydrate aqueous solutions (30mL), are cooled to 0 DEG C, stir 10 minutes, then di-tert-butyl dicarbonate is added dropwise 6.55g, (30.0mmol) (is dripped off) in 60 minutes, slow heating, is stirred 6 hours or is stayed overnight at room temperature.Reaction solution 2mol/L Watery hydrochloric acid adjusts pH=4, is extracted, washed 3 times with ethyl acetate/aqueous systems, merge organic phase, anhydrous sodium sulfate drying obtains white Color solid boc-L- proline 3 .78g, yield 88%.
(ii) 100mL single-necked flasks, are separately added into boc-L- proline 1.46g (6.8mmol), α-kakuol in (i) 1.01g (4.5mmol), DMAP 0.22g (1.8mmol), dichloromethane (30mL), after stirring 30 minutes at room temperature, add EDCI 1.73g (9.0mmol), reacts 6 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, adds saturated sodium bicarbonate Solution, adjusts pH=7-8, and ethyl acetate extraction is separated 3 times, merges organic phase, and anhydrous sodium sulfate drying, suction filtration is depressurized dense Contracting, gained crude product is through the isolated yellow solid boc-L- proline α-kakuol 1.10g of silica gel chromatographic column, yield 58%.
(iii) 100mL single-necked flasks, be separately added into boc-L- proline α in (ii)-kakuol 0.97g (2.3mmol), Dichloromethane (10mL), is added dropwise under the protection of trifluoroacetic acid (3mL) nitrogen, is stirred at room temperature 5 hours, after being concentrated under reduced pressure, add acetic acid Ethyl ester (20mL), water (20mL), saturated sodium bicarbonate aqueous solution (50mL), extract and separate 3 times merges organic phase, anhydrous slufuric acid Sodium is dried, and suction filtration is concentrated under reduced pressure, and obtains light yellow solid L-PROLINE α-kakuol 0.69g, yield 93%.
Embodiment 6：
3,4 ,-dihydroxycinnamic acid α-asarum alcohol ester
100mL single-necked flasks, 0 DEG C of addition α-kakuol 1.79g (8.0mmol), Caffeic acid 2.16g (12.0mmol), tetrahydrofuran (30mL), triphenyl phosphorus 2.10g (8.0mmol), diisopropyl azodiformate 1.62g (8.0mmol), is stirred 36 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, is extracted with ethyl acetate/aqueous systems Take, wash 3 times, merge organic phase, anhydrous sodium sulfate drying, suction filtration is concentrated under reduced pressure, and gained crude product is obtained through silica gel chromatograph post separation To yellow solid 1.24g, yield 40%.
Embodiment 7：
3,4 ,-dihydroxyphenyl acetic acid α-asarum alcohol ester
100mL single-necked flasks, 0 DEG C of addition α-kakuol 1.68g (7.5mmol), DOPAC 1.90g (11.3mmol), tetrahydrofuran (30mL), triphenyl phosphorus 1.97g (7.5mmol), diisopropyl azodiformate 1.52g (7.5mmol), is stirred 40 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, is extracted with ethyl acetate/aqueous systems Take, wash 3 times, merge organic phase, anhydrous sodium sulfate drying, suction filtration is concentrated under reduced pressure, and gained crude product is obtained through silica gel chromatograph post separation To yellow solid 1.23g, yield 44%.
Embodiment 8：
3- nitrophenyl-acetic acids α-asarum alcohol ester
100mL single-necked flasks, are separately added into α-kakuol 1.57g (7.0mmol), 3- nitrophenyl-acetic acids 1.90g (10.5mmol), DMAP 0.26g (2.1mmol), DMF (30mL), after stirring 30 minutes at room temperature, are added EDCI 2.01g (10.5mmol), react 6 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, add saturated carbon Sour hydrogen sodium solution, adjusts pH=7-8, is extracted, washed 3 times with ethyl acetate/aqueous systems, merges organic phase, and anhydrous sodium sulfate is done Dry, suction filtration is concentrated under reduced pressure, and gained crude product is through the isolated yellow solid 0.81g of silica gel chromatographic column, yield 30%.
Embodiment 9：
2,5- methoxy cinnamic acids α-asarum alcohol ester
100mL single-necked flasks, are separately added into α-kakuol 0.90g (4.0mmol), 2,5- methoxy cinnamic acids 1.25g (6.0mmol), DMAP 0.15g (1.2mmol), dichloromethane (20mL), after stirring 30 minutes at room temperature, add EDCI 1.15g (6.0mmol), reacts 9 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, adds saturated sodium bicarbonate Solution, adjusts pH=7-8, is extracted, washed 3 times with ethyl acetate/aqueous systems, merge organic phase, anhydrous sodium sulfate drying is taken out Filter, is concentrated under reduced pressure, gained crude product is through the isolated yellow solid 1.03g of silica gel chromatographic column, yield 62%.
Embodiment 10：
P-methoxycinnamic acid α-asarum alcohol ester
100mL single-necked flasks, are separately added into α-kakuol 0.67g (3.0mmol), p-methoxycinnamic acid 0.80g (4.5mmol), DMAP 0.11g (0.9mmol), dichloromethane (20mL), after stirring 30 minutes at room temperature, add EDCI 0.86g (4.5mmol), reacts 6 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, adds saturated sodium bicarbonate Solution, adjusts pH=7-8, is extracted, washed 3 times with ethyl acetate/aqueous systems, merge organic phase, anhydrous sodium sulfate drying is taken out Filter, is concentrated under reduced pressure, gained crude product is through the isolated yellow solid 0.69g of silica gel chromatographic column, yield 60%.
Embodiment 11：
Parachlorobenzoic-acid α-asarum alcohol ester
100mL single-necked flasks, are separately added into α-kakuol 0.45g (2.0mmol), parachlorobenzoic-acid 0.47g (3.0mmol), DMAP 0.07g (0.6mmol), dichloromethane (20mL), after stirring 30 minutes at room temperature, add EDCI 0.58g (3.0mmol), reacts 6 hours at room temperature, TLC monitoring reactions, after raw material reaction terminates, adds saturated sodium bicarbonate Solution, adjusts pH=7-8, is extracted, washed 3 times with ethyl acetate/aqueous systems, merge organic phase, anhydrous sodium sulfate drying is taken out Filter, is concentrated under reduced pressure, gained crude product is through the isolated yellow solid 0.35g of silica gel chromatographic column, yield 48%.
Embodiment 12：
Propionic acid α-asarum alcohol ester
100mL single-necked flasks, add propionic acid 0.28g (3.8mmol), under condition of ice bath, add thionyl chloride (12mL), Backflow 3 hours, is cooled to addition tetrahydrofuran in room temperature, the excessive thionyl chloride of vacuum distillation, residue and is sufficiently stirred for, obtain Propionyl chloride tetrahydrofuran solution；Under condition of ice bath, α-kakuol 0.56g (2.5mmol), pyridine 0.60g is separately added into (7.6mmol), propionyl chloride tetrahydrofuran solution, is stirred 15 minutes, then temperature rising reflux 3 hours, after reaction completely, and cooling is filtered to remove Tetrahydrofuran is evaporated off in pyridine hydrochloride, filtrate decompression, and ethyl acetate/water separation merges organic phase, anhydrous sodium sulfate drying is taken out Filter, is concentrated under reduced pressure, gained crude product is through the isolated yellow solid 0.44g of silica gel chromatographic column, yield 65%.
The activity research of 3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester
3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester, which is used to treat, faints from fear and epilepsy.Used anti-epileptic pharmacological evaluation The antiepileptic exploitation program that Bian NIHs (NIH) implement.Maximum electricity including evaluating Kang Epilepsy epilepsys activity Convulsions experimental method (MES) and the rotary process (Rotarodtest) for investigating neurotoxicity.Exist to further study and evaluate medicine Anticonvulsion pharmacological mechanism in different chemical models, is commented using 2 kinds of classical chemical models such as pentylenetetrazole, 3- mercaptopropionic acids Valency.
(1) maximum electrofit experiment (MES)
MES is the common experimental model of grand mal, if test-compound can significantly resist MES, the compound has The effective medicine of clinical treatment grand mal may be developed into.
Method：KM mouse carry out preliminary screening before the test, it is qualified after can be used for next step experiment.Screening technique is such as Under：The previous day is tested, 15V is used to experiment mice, 60Hz electro photoluminescence, two electrodes are sandwiched in mouse ears, and energization is irritated , there is the tetanic mouse of hind leg and belongs to the standby mouse of experiment, for later experiments in 0.45s.Anti- maximum electrofit measuring side Method is：After test-compound dissolving, gastric infusion, 0.25h, 0.5h, 1h, 2h, 3h, 4h use 0.45s upon administration respectively, 15V, 60Hz ear electrode stimulating, if to occur without hind leg tetanic for mouse, show that the test-compound has at this dose Anti-convulsant activity.According to certain administration rule, gradient concentration is designed, the tested chemical combination of different gradient concentrations is given respectively Thing, its anti-convulsant activity of observed and recorded finally calculates the effective dose 50 (ED of the anti-maximum vulsant activity of test-compound50)。 Calculated according to following formula：
ED50=lg-1[Xm-i(∑P-0.5)]
SX50=i (∑ P- ∑s P2/n-1)1/2
ED5095% fiducial limit=lg-1(lgED50±1.96SX50)
The meaning of symbol is as follows in formula：
The common logarithm of Xm maximum doses；
The common logarithm of ratio value between i dosage；
The positive rate that every group of P, with fractional representation；
The number of animals that every group of n；
SX50 lgED50Standard error；
The mouse anticonvulsion experimental result at initial stage (i.g) of table 1.3,4,5- trimethoxy cinnamic acids α-asarum alcohol estera
aTest-compound adds tween water dissolves；
b0.25h, 0.5h, 1h, 2h, 3h, 4h carry out maximum electrofit experiment after gastric infusion；
cIt is 6 to test mouse quantity；
d ED50For effective dose 50；
e95% confidence limit provided in bracket；
(2) neurotoxicity experiment (Neurotoxicity)
Method：Experiment mice gastric infusion, mouse is placed on transfer rod formula by 0.25h, 0.5h, 1h, 2h upon administration respectively On tired instrument, with 16 revs/min of rotations.Test mice is not fallen or fallen within 3 times in 3min, indicates that the compound exists There is no neurotoxicity under the dosage；Fall more than 3 times and then think that the compound has neurotoxicity at this dose.According to administration rule Rule design gradient concentration, gives the test-compound of different graded doses, calculates median toxic dose (TD respectively50).According to following Formula calculated：
TD50=lg-1[Xm-i(∑P-0.5)]
SX50=i (∑ P- ∑s P2/n-1)1/2
TD5095% fiducial limit=lg-1(lgTD50±1.96SX50)
The meaning of symbol is as follows in formula：
The common logarithm of Xm maximum doses；
The common logarithm of ratio value between i dosage；
The positive rate that every group of P, with fractional representation；
The number of animals that every group of n；
SX50 lgTD50Standard error；
The mouse Nerve toxicity test of table 2.3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester and anti-convulsant activity data Analyze (i.g)a
aTest-compound adds tween water dissolves；
b0.25h, 0.5h, 1h, 2h carry out neurotoxicity experiment after gastric infusion；
cIt is 4 to test mouse quantity；
d TD50For median toxic dose；
e ED50For effective dose 50；
fPI is protective index (TD50/ED50)；
g95% confidence limit provided in bracket；
Calculated by the experimental data after measure, 3,4,5- trimethoxy cinnamic acid α-asarum alcohol ester is in gastric infusion The ED of the lower maximum electrofit experiment of confrontation50=90.3mg/kg, TD50=939.7mg/kg, protective index PI are 10.4, are shown Good anti-convulsant activity, and overt toxicity is not shown.
In order to be inferred to 3,4,5- trimethoxy cinnamic acid α-possible anticonvulsion mechanism of asarum alcohol ester, this research uses penta The chemical test models such as tetrazolium, 3- mercaptopropionic acids are to test-compound (i.g：160mg/kg, 80mg/kg, 40mg/kg) it is preliminary Anti-convulsant activity is evaluated.
(3) the experimental epilepsy model that pentylenetetrazole induces
Method：Experiment mice is randomly divided into 5 groups, respectively administration group (i.g：160mg/kg、80mg/kg、40mg/kg)、 Control group and blank group, every group 6, administration group gavage test-compound, control group gavage positive drug carbamazepine, blank group is filled Stomach physiological saline, after 30 minutes, gives gavage pentylenetetrazole 200mg/kg, animal subject is individually placed in a mouse cage and observes 60 Minute, record latent time, Myoclonic seizures number, tonic seizures number and the death of every group of mouse Myoclonic seizures Number.
Table 3.3,4,5- trimethoxy cinnamic acids α-mouse anti-convulsant activity result caused by asarum alcohol ester confrontation pentylenetetrazole
* is compared p with physiological saline group<0.01；* p is compared with physiological saline group<0.05
In the convulsion model experiment of confrontation pentylenetetrazole chemicals induction, compared with physiological saline group, under test dose The 3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester of (160mg/kg, 80mg/kg, 40mg/kg) can significantly extend mouse battle array Time (the p of contraction breaking-out<0.05) it, and can suppress mouse tonic seizures, reduce mouse death rate；Compared with carbamazepine, 3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester suppresses tonic seizures to test mice and reduces the death rate under Isodose Effect is suitable.Pentylenetetrazole is to cause convulsions by suppressing γ-aminobutyric acid (GABA) neurotransmitter, and GABA is present in brain Major inhibitory neurotransmitter, have inseparable relation with epilepsy.According to the trimethoxy cinnamic acid α of table 3,3,4,5-- Asarum alcohol ester may be by increasing GABA neurotransmitters, to suppress or reduce the mice against seizure of pentylenetetrazole induction.
(4) the experimental epilepsy model that 3- mercaptopropionic acids induce
Method：Experiment mice is randomly divided into 5 groups, respectively administration group (i.g：160mg/kg、80mg/kg、40mg/kg)、 Control group and blank group, every group 6, administration group gavage test-compound, control group gavage positive drug carbamazepine, blank group is filled Stomach physiological saline, after 30 minutes, gives gavage 3- mercaptopropionic acid 60mg/kg, animal subject is individually placed in a mouse cage and seen Examine 60 minutes, record latent time of every group of mouse Myoclonic seizures, Myoclonic seizures number, tonic seizures number and dead Die number.
Table 4.3,4,5- trimethoxy cinnamic acids α-mouse anti-convulsant activity caused by asarum alcohol ester confrontation 3- mercaptopropionic acids As a result
* p is compared with physiological saline group<0.05
In the convulsion model experiment of confrontation 3- mercaptopropionic acids chemicals induction, compared with physiological saline group, 160mg/ Kg, 80mg/kg 3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester can significantly extend the time (p of mouse Myoclonic seizures< 0.05) it, and can suppress mouse Myoclonic seizures and tonic seizures, reduce mouse death rate；Compared with carbamazepine, 160mg/ Kg, 80mg/kg 3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester suppress tonic seizures to test mice and reduced dead Rate effect is suitable.3- mercaptopropionic acids are GABA synzyme glutamate decarboxylase competitive inhibitors, and the synthesis that can suppress GABA is led GABA intracerebrals level is caused to reduce.3,4,5- trimethoxy cinnamic acids α-asarum alcohol ester can moderately resist the frightened of 3- mercaptopropionic acids induction Faint, illustrate that 3,4,5- trimethoxy cinnamic acid α-asarum alcohol ester may activate GABA synzyme glutamate decarboxylase or suppress intracerebral GABA。

Claims (8)

1. α-asarum alcohol ester, it is characterised in that its general structure is shown in formula I：
Wherein：
R is：
2. the preparation method of α as claimed in claim 1-asarum alcohol ester, it is characterised in that method includes：By Compounds of formula II With compound of formula III, catalyst in molar ratio 1.0~2.0:1.0~2.0:0.1~1.0 sequentially adds containing appropriate organic In solvent reaction container, until completely dissolved, dehydrating agent is added, the mol ratio of dehydrating agent and Compounds of formula II is 1~2: 1, it is stirred at room temperature 5-20 hours, stops reaction, ethyl acetate/water separation, organic phase anhydrous sodium sulfate drying, concentration, post color Spectrum is isolated and purified；
The catalyst is pyridine, 2,4,6- trimethylpyridines, 2,6- lutidines, 2,6- di-t-butyl -4- picolines With one kind in DMAP or be wherein combined；
The organic solvent be dichloromethane, chloroform, tetrachloromethane, tetrahydrofuran, ethyl acetate, methyl tertiary butyl ether(MTBE), Ether, 1,4- dioxane, N,N-dimethylformamide, 1-METHYLPYRROLIDONE, DMAC N,N' dimethyl acetamide and dimethyl are sub- It is a kind of or be wherein combined in sulfone；
The dehydrating agent be dicyclohexylcarbodiimide, 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides or DIC.
3. the preparation method of α described in claim 1-asarum alcohol ester, it is characterised in that method includes：
α-kakuol generates α-asarum alcohol ester with compound of formula III under Mitsunobu reaction conditions：
4. preparation method as claimed in claim 3, it is characterised in that method includes：By α-kakuol, general formula compound, idol Nitrogen compound, organic phosphorus compound are 1~1.5 in molar ratio:1~1.5:1~1.5:1~1.5 is dissolved in dry tetrahydrofuran In, react at room temperature 10-48 hours, ethyl acetate/water separation, organic phase anhydrous sodium sulfate drying, concentration, pillar layer separation is pure Change.
5. preparation method as claimed in claim 4, it is characterised in that the azo-compound be diethyl azodiformate, Diisopropyl azodiformate, azodicarbonyldipiperidine, N, N, N ', N '-tetramethyl azodicarboxy acid amides, N, N, N ', N '-four Isopropyl azodicarboxy acid amides or the azepine Xin Yin -3,8- diketone of 4,7- dimethyl -3,4,5,6,7,8- hexahydros -1,2,4,7- four.
6. preparation method as claimed in claim 4, it is characterised in that the organic phosphorus compound be triphenylphosphine, tributylphosphine or Trimethyl phosphorus.
7. the mixture of the alloisomerism of compound described in claim 1 or its different Stereoisomeric compounds.
8. compound described in claim 1 or 7 be used to preparing it is calm, calm the nerves, anti-senile dementia, anticonvulsion, anti-epileptic, antidepression The application of medicine.
CN201410699506.6A 2014-11-26 2014-11-26 α asarum alcohol esters and preparation method and application Active CN104529775B (en)

Priority Applications (19)

Application Number Priority Date Filing Date Title
CN201410699506.6A CN104529775B (en) 2014-11-26 2014-11-26 α asarum alcohol esters and preparation method and application
MYPI2017701893A MY175619A (en) 2014-11-26 2015-11-26 A-asary-laldehyde ester, preparation method therefor, and application thereof
AU2015353112A AU2015353112B2 (en) 2014-11-26 2015-11-26 Alpha-asary-laldehyde ester, preparation method therefor, and application thereof
US15/529,283 US10131619B2 (en) 2014-11-26 2015-11-26 α-Asary-laldehyde ester, preparation method therefor, and application thereof
RU2017121591A RU2673887C1 (en) 2014-11-26 2015-11-26 Compound a-azari-aldehyde ether, method for production and application thereof
JP2017527866A JP6506841B2 (en) 2014-11-26 2015-11-26 α-Asaryl aldehyde ester, process for preparing it and use thereof
SI201531204T SI3225616T1 (en) 2014-11-26 2015-11-26 Alpha-asary-laldehyde ester, preparation method therefor, and application thereof
KR1020177017335A KR102029898B1 (en) 2014-11-26 2015-11-26 α-ASARY-LALDEHYDE ESTER, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF
SG11201704239PA SG11201704239PA (en) 2014-11-26 2015-11-26 α-ASARY-LALDEHYDE ESTER, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF
DK15863145.7T DK3225616T3 (en) 2014-11-26 2015-11-26 ALPHA-ASARY LALDEHYESTER, PROCEDURE FOR PREPARING IT AND USING IT
PCT/CN2015/095686 WO2016082780A1 (en) 2014-11-26 2015-11-26 α-ASARY-LALDEHYDE ESTER, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF
EP15863145.7A EP3225616B1 (en) 2014-11-26 2015-11-26 Alpha-asary-laldehyde ester, preparation method therefor, and application thereof
PL15863145T PL3225616T3 (en) 2014-11-26 2015-11-26 Alpha-asary-laldehyde ester, preparation method therefor, and application thereof
CA2968652A CA2968652C (en) 2014-11-26 2015-11-26 Esters of .alpha.-asaronol, methods of preparation and uses thereof
NZ732395A NZ732395A (en) 2014-11-26 2015-11-26 Α-asary-laldehyde ester, preparation method therefor, and application thereof
HUE15863145A HUE049249T2 (en) 2014-11-26 2015-11-26 Alpha-asary-laldehyde ester, preparation method therefor, and application thereof
IL252461A IL252461B (en) 2014-11-26 2017-05-23 Alpha-asary-laldehyde ester, preparation method therefor, and application thereof
HK18103381.1A HK1243995A1 (en) 2014-11-26 2018-03-12 Alpha-asary-laldehyde ester, preparation method therefor, and application thereof
CY20201100376T CY1123193T1 (en) 2014-11-26 2020-04-27 A-ASARYL-ALDEHYDE ESTER, METHOD OF PREPARATION THEREOF AND ITS APPLICATION

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410699506.6A CN104529775B (en) 2014-11-26 2014-11-26 α asarum alcohol esters and preparation method and application

Publications (2)

Publication Number Publication Date
CN104529775A CN104529775A (en) 2015-04-22
CN104529775B true CN104529775B (en) 2017-07-14

Family

ID=52845460

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410699506.6A Active CN104529775B (en) 2014-11-26 2014-11-26 α asarum alcohol esters and preparation method and application

Country Status (19)

Country Link
US (1) US10131619B2 (en)
EP (1) EP3225616B1 (en)
JP (1) JP6506841B2 (en)
KR (1) KR102029898B1 (en)
CN (1) CN104529775B (en)
AU (1) AU2015353112B2 (en)
CA (1) CA2968652C (en)
CY (1) CY1123193T1 (en)
DK (1) DK3225616T3 (en)
HK (1) HK1243995A1 (en)
HU (1) HUE049249T2 (en)
IL (1) IL252461B (en)
MY (1) MY175619A (en)
NZ (1) NZ732395A (en)
PL (1) PL3225616T3 (en)
RU (1) RU2673887C1 (en)
SG (1) SG11201704239PA (en)
SI (1) SI3225616T1 (en)
WO (1) WO2016082780A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104529775B (en) * 2014-11-26 2017-07-14 西北大学 α asarum alcohol esters and preparation method and application
KR102473931B1 (en) * 2016-08-04 2022-12-02 다카사고 고료 고교 가부시키가이샤 Warming sensation compounds
CN113248380B (en) * 2020-11-23 2023-01-10 西北大学 Synthetic method of acetic acid alpha-asaryl alcohol ester and alpha-fine octanol
CN113387804B (en) * 2021-06-04 2023-05-02 西安石油大学 Synthesis method of alpha-asarone acetate and alpha-octanol

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2091366C1 (en) * 1992-06-16 1997-09-27 Инесса Ивановна Крицкая Bicyclo (2,2,2) octane-2-carboxylic acid sodium salt having anticonvulsion activity
JP2009543758A (en) * 2006-03-16 2009-12-10 モレアク プライベート リミテッド Combination therapy for treatment of patients with neurological disorders and cerebral infarction
CN101015543B (en) * 2007-02-15 2010-07-07 浙江海正药业股份有限公司 Use of cinnamic acid and allyl benzoate compound with oxidation resistance function for protecting liver and brain damage
CN101085129B (en) * 2007-07-11 2010-11-10 石任兵 Acorus gramineus total phenylpropanoid extraction preparation method
CN101215226B (en) * 2008-01-02 2011-06-01 湖南师范大学 Method for synthesizing alpha-asarone
CN101974011B (en) * 2010-10-26 2012-01-04 云南生物谷灯盏花药业有限公司 New compound methyl brevicate with medical activity
CN102648937A (en) * 2011-02-24 2012-08-29 中国医学科学院药用植物研究所 Application of polygala alkaline hydrolysis product composition in preparation of anti-senile dementia medicine
CN104529775B (en) 2014-11-26 2017-07-14 西北大学 α asarum alcohol esters and preparation method and application
CN104529724B (en) * 2014-11-26 2016-11-02 西北大学 α-kakuol and preparation method and application

Also Published As

Publication number Publication date
HK1243995A1 (en) 2018-07-27
US20170260122A1 (en) 2017-09-14
HUE049249T2 (en) 2020-09-28
US10131619B2 (en) 2018-11-20
MY175619A (en) 2020-07-02
CA2968652A1 (en) 2016-06-02
PL3225616T3 (en) 2020-07-27
DK3225616T3 (en) 2020-06-02
EP3225616A4 (en) 2018-07-11
KR102029898B1 (en) 2019-10-08
SG11201704239PA (en) 2017-06-29
EP3225616B1 (en) 2020-03-04
JP2018503602A (en) 2018-02-08
CN104529775A (en) 2015-04-22
CA2968652C (en) 2020-07-07
WO2016082780A1 (en) 2016-06-02
JP6506841B2 (en) 2019-04-24
SI3225616T1 (en) 2020-07-31
AU2015353112A1 (en) 2017-06-22
AU2015353112B2 (en) 2018-07-05
KR20170086636A (en) 2017-07-26
CY1123193T1 (en) 2021-10-29
NZ732395A (en) 2018-06-29
EP3225616A1 (en) 2017-10-04
IL252461B (en) 2020-07-30
RU2673887C1 (en) 2018-12-03
IL252461A0 (en) 2017-07-31

Similar Documents

Publication Publication Date Title
US11154530B2 (en) Pharmaceutical composition for treating liver cancer, comprising tetraarsenic hexoxide crystalline polymorph
CN104529775B (en) α asarum alcohol esters and preparation method and application
LU84157A1 (en) NOVEL 1,2-DIAMINOCYCLOBUTENE-3,4-DIONES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
CN102212093B (en) Flavonoid glycoside compounds, method for preparing same and application
CN112300141A (en) Quinazoline-containing myricetin derivative, and preparation method and application thereof
CN106278857A (en) α, β unsaturated carbonyl tetralone derivative and application thereof
CN102659863B (en) A kind of separation purifying technique of TSG
EP3279200A1 (en) Crystal of 5-((2-(6-amino)-9h-purin-9-yl)ethyl)amino)pentan-1-ol
CN110857285B (en) Substituted pyrazole compound, preparation method, pharmaceutical composition and application thereof
CN107082754A (en) A kind of cinnamic acid derivative with aldose reductase inhibition activity and its production and use
CN105439889B (en) A kind of vanillic aldehyde amine noval chemical compound, its preparation method and medical usage
CN105237487B (en) The chalcone of base containing ligustrazine virtue oxygen alkane acid compounds, preparation method and applications
CN104292293A (en) Preparation method of dutasteride impurity I
CN109503351A (en) A kind of chalcone derivative containing allylic structure and its application
CN110194746B (en) Compound for treating alzheimer disease, preparation method and application thereof
CN110194743B (en) Phenyl (3-methoxy-4- (4-methyl-1H-imidazole-1-yl) phenyl) ketone compound
CN110194764B (en) Amide compound, preparation method and application thereof
JP7348214B2 (en) Crystal forms of HDAC6 selective inhibitors and uses thereof
CN108261414B (en) A kind of pharmaceutical composition for treating lung cancer
CN110194744B (en) Compound for inhibiting beta-amyloid protein generation and preparation method and application thereof
CN113402414A (en) Benzoic acid derivative and preparation method and pharmaceutical application thereof
WO2021042911A1 (en) Magl inhibitor, preparation method therefor and use thereof
CN107311973A (en) A kind of derivative of dihydromyricetin containing itrate group and its preparation and application
CN109020830A (en) A kind of methylol cyclopropyl acetonitrile derivative and its methods for making and using same
CN107629040A (en) A kind of flavanone alcohols compound of the heteroaromatic containing N and its preparation method and application

Legal Events

Date Code Title Description
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant